Characterization of C4–2 Prostate Cancer Bone Metastases and Their Response to Castration

Abstract

New well-characterized preclinical models of prostate cancer (CaP) bone metastases are needed to improve our understanding of the development of CaP-related bone disease in patients. Here we describe characterization of a model consisting of direct injection of C4-2 cells into tibias.Introduction: Prostate cancer (CaP) has a high proclivity to metastasize to bone. Development and characterization of preclinical models of CaP bone metastases are of high interest. The objective of this study was to characterize C4-2 bone metastases and their response to castration. Materials and Methods: Cell suspensions of C4-2, a subline of LNCaP, were injected directly into the tibias of intact male mice. In groups A (n ϭ 7) and B (n ϭ 5), animals were killed 3 and 8 weeks after injection of C4-2 cells, respectively. In group C (n ϭ 7), animals were castrated 3 weeks after injection and killed 5 weeks after castration. Serum prostate-specific antigen (PSA) levels and bone mineral density (BMD) were measured, and bone histomorphometric analysis was performed. Results: C4-2 cells decreased BMD of the injected tibias by 36.1% and bone volume by 74.1% versus normal tibias. Castration caused a 32.3% drop in serum PSA (p ϭ 0.0438), with a nadir at day 14, after which it began to rise again. Bone destruction in the tumorous tibias of castrated animals was decreased by 15.9% versus tumorous tibias of intact animals (p ϭ 0.0392). However, BMD in the tumorous tibias of castrated mice was still lower than in normal tibias of intact animals. Castration also decreased BMD and bone volume in nontumorous tibias (p ϭ 0.0406 and 0.0232, respectively). Conclusions:The C4-2 model of bone metastasis recapitulates the response to androgen deprivation observed in CaP patients with bone metastases and is suitable for study of interactions between tumor and bone cells and evaluation of new therapeutic modalities.

Human Osteocalcin and Bone Sialoprotein Mediating Osteomimicry of Prostate Cancer Cells: Role of cAMP-Dependent Protein Kinase A Signaling Pathway

“…progression using this LNCaP prostate cancer progression model (57)(58)(59). To further understand differences in responsiveness among prostate cancer and bone stromal cells to soluble factors in conditioned medium, we must isolate and characterize the responsible factors and evaluate cell surface or intracellular receptors coupling to cell signaling systems in prostate cancer and bone cells.…”

Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis

“…We have previously published that despite the stimulation of bone formation by the growth of C4-2 cells in the tibiae, tumoured tibiae showed decreases in BMD and trabecular bone volume (Pfitzenmaier et al, 2003;Morrissey et al, 2007). Knowing the significant role src plays in the regulation of osteoclast activity, we, therefore, examined alterations in BMD in tibiae of animals treated with dasatinib.…”

RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid

“…Four-to 6-week-old male SCID mice (Fox Chase SCID mice, Charles River, Wilmington, MA) were injected with approximately 2 × 10 5 cells into the proximal end of the right tibia as we have described previously [33][34][35]. Tumor growth was monitored by serum levels of prostate specific antigen (PSA).…”